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Regulated necrosis pathways

机译：坏死调节途径

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Several types of regulated necrosis exist in addition to necroptosis (reviewed in ref. 2). Parthanatos involves hyperactivation of poly(ADP-ribose) (PAR) polymerase 1 (PARP1), an enzyme originally characterized by its role in DNA-repair mechanisms following a DNA-damage response. The massive PARylation of target proteins leads to cellular depletion of NAD~+ (and consequently of ATP), resulting in a bioenergetic crisis and a form of regulated necrosis. The term ferroptosis was recently coined to describe a type of regulated necrosis that is characterized by iron-dependent production of reactive oxygen species (ROS), which can be blocked by the iron chelator desferrioxamine (DFO). It is elicited by pharmacological inhibition of the antiporter system x_c~-, which exchanges extracellular cystine for intracellularglutamate. Glutamate toxicity on neurons works by blocking the same antiporter system and has been termed oxytosis. Mitochondrial permeability transition (MPT)-mediated regulated necrosis is another cell-death modality. Cyclophilin D (CYPD) is the sole genetically confirmed component of the permeability transition pore complex (PTPC), which is implicated in MPT-mediated regulated necrosis. Pyroptosis and pyronecrosis are highly inflammatory cell-death modalities characterized by cellular swelling and plasma membrane permeabilization. Pyroptosis occurs after canonical and non-canonical inflammasome stimulation, leading to caspase-1 and caspase-11 activation, respectively. Some reports distinguish pyronecrosis as a cell-death modality occurring during infection that does not depend on caspase-1 or caspase-11, but requires cathepsin B release following lysosomal membrane permeabilization. NETosis/ETosis (NET is neutrophil extracellular trap; ET is extracelluartrap) is also implicated in protection against microbial and viral infection. This modality occurs in neutrophils, eosinophils, mast cells and macrophages. It is associated with chromatin decondensation and release of NETs, which are composed of DNA, chromatin and histones, and allow immune cells to immobilize and kill infectious agents. Besides apoptosis and the various forms of regulated necrosis, a third modality is often put forward: autophagic cell death. The name is slightly misleading because autophagy is in the first instance a crucial mechanism in cellular homeostasis and adaptive responses, however, it can also become a cell-death mechanism. Autophagic cell death is biochemically characterized by markers of autophagy such as lipidation of LC3 (microtubule-associated protein 1 light chain 3) and the degradation of p62, a ubiquitin-binding scaffold protein, and blocked by genetically or pharmacologically targeting the members of the autophagy pathway. Inhibitors that interfere with cell death modalities are shown in Table 1.
机译：除坏死病外，还存在几种类型的调节性坏死（参见参考文献2）。 Parthanatos涉及聚（ADP-核糖）（PAR）聚合酶1（PARP1）的超活化，该酶最初的特征是其在DNA损伤反应后在DNA修复机制中的作用。靶蛋白的大量PARylation导致NAD〜+（进而是ATP）的细胞耗竭，从而导致生物能危机和某种形式的坏死。最近创造了术语肥大病来描述一种受调节的坏死，其特征是依赖铁的活性氧（ROS）产生，该活性氧可以被铁螯合剂去铁胺（DFO）阻断。它是由抗转运蛋白系统x_c〜-的药理学抑制引起的，该系统将胞外胱氨酸交换为胞内谷氨酸。谷氨酸对神经元的毒性可通过阻断相同的反向转运系统发挥作用，被称为氧化病。线粒体通透性转变（MPT）介导的调节性坏死是另一种细胞死亡方式。亲环蛋白D（CYPD）是通透性转换孔复合物（PTPC）的唯一经遗传学证实的成分，与MPT介导的调节性坏死有关。焦化和焦烧坏死是高度炎性的细胞死亡方式，其特征在于细胞肿胀和质膜透化。在典型和非典型的炎症小体刺激后发生细胞凋亡，分别导致caspase-1和caspase-11活化。一些报告将吡咯菌坏死区分为感染期间发生的一种细胞死亡方式，它不依赖于caspase-1或caspase-11，但在溶酶体膜透化后需要组织蛋白酶B释放。 NETosis / ETosis（NET是嗜中性粒细胞胞外陷阱； ET是extracelluartrap）也涉及防止微生物和病毒感染。这种形态发生在嗜中性粒细胞，嗜酸性粒细胞，肥大细胞和巨噬细胞中。它与染色质的缩聚和NETs的释放有关，NETs由DNA，染色质和组蛋白组成，并允许免疫细胞固定并杀死感染因子。除了凋亡和各种形式的坏死调节外，还经常提出第三种方式：自噬细胞死亡。这个名字有点误导，因为自噬首先是细胞动态平衡和适应性反应的关键机制，但是，它也可以成为细胞死亡的机制。自噬细胞死亡的生化特征是自噬的标志物，例如LC3（微管相关蛋白1轻链3）的脂质化和泛素结合支架蛋白p62的降解，并通过遗传或药理作用靶向自噬成员途径。表1显示了干扰细胞死亡方式的抑制剂。

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    《Nature》 |2015年第7534期|312-312|共1页
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  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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